Berberine inhibits palmitate-induced NLRP3 inflammasome activation by triggering autophagy in macrophages: A new mechanism linking berberine to insulin resistance improvement
Berberine inhibits palmitate-induced NLRP3 inflammasome activation by triggering autophagy in macrophages: A new mechanism linking berberine to insulin resistance improvement
复制标题
小檗碱通过触发巨噬细胞自噬抑制棕榈酸诱导的 NLRP3 炎症小体激活：小檗碱与胰岛素抵抗改善联系的新机制
DOI：
10.1016/j.biopha.2017.03.003
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发表时间：
2017-05-01
影响因子：
7.5
通讯作者：
Xu, Qiang
中科院分区：
文献类型：
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作者：
Zhou, Hang;Feng, Lili;Xu, Qiang
已有研究报道，NLRP3（含NOD样受体家族吡咯蛋白结构域3）炎症小体与肥胖诱导的炎症反应及胰岛素抵抗有关。然而，目前针对NLRP3炎症小体治疗胰岛素抵抗的药物却寥寥无几。在本研究中，我们发现黄连素（BBR）可显著抑制饱和脂肪酸棕榈酸（PA）诱导的巨噬细胞中NLRP3炎症小体激活及白细胞介素-1β（IL-1β）的释放，而IL-1β是脂肪组织胰岛素敏感性的重要介质之一。BBR处理可显著上调巨噬细胞的自噬水平，而敲低beclin1及使用自噬抑制剂则会逆转BBR对炎症小体的抑制作用。此外，AMPK（单磷酸腺苷活化蛋白激酶）抑制剂9-β -D-阿拉伯呋喃糖基腺嘌呤（Ara-A）可阻断BBR的大部分作用，这表明AMPK信号通路可能参与了BBR诱导的巨噬细胞自噬过程。重要的是，在高脂饮食诱导的胰岛素抵抗模型中，BBR还可预防NLRP3炎症小体依赖性炎症反应及代谢紊乱。与对照组小鼠相比，过继转移经BBR处理、由脂多糖（LPS）加棕榈酸 - 牛血清白蛋白（PA-BSA）诱导的骨髓来源巨噬细胞（BMDMs），可显著改善ob/ob小鼠的胰岛素抵抗。然而，BMDMs与自噬抑制剂3 - 甲基腺嘌呤（3-MA）共同处理几乎可完全逆转BBR的作用。综上所述，BBR通过激活脂肪组织巨噬细胞（ATMs）中依赖AMPK的自噬发挥其抗炎作用。本研究进一步阐明了BBR的作用机制及其在减轻胰岛素抵抗方面的潜力。（C）2017爱思唯尔马松出版公司 版权所有
NLRP3 (Nod-like receptor family pyrin domain containing 3) inflammasome has been reported to contribute to obesity-induced inflammation and insulin resistance. However, there are few drugs targeting NLRP3 inflammasome for the treatment of insulin resistance. In the present study, we showed that berberine (BBR) significantly suppressed saturated fatty acid palmitate (PA)-induced NLRP3 inflammasome activation and interleukin-1 beta (IL-1 beta) release in macrophages, which was one of the most important mediators in the insulin sensitivity of adipose tissue. BBR treatment dramatically upregulated macrophage autophagic level while knockdown beclin1 and autophagy inhibitor reversed BBR's suppression on inflammasome. Furthermore, AMPK (adenosine monophosphate-activated protein kinase) inhibitor Adenine 9-beta-D-arabinofuranoside (Ara-A) blocked most effects of BBR, suggesting that AMPK signals may be involved in BBR-induced macrophage autophagy. Importantly, BBR also prevented NLRP3 inflammasome-dependent inflammation and metabolic disorder in a high-fat-diet-induced insulin resistance model. Adoptive transfer of BBR-treated bone marrow-derived macrophages (BMDMs), which was induced by lipopolysaccharide (LPS) plus palmitate-bovine serum albumin (PA-BSA), significantly ameliorated insulin resistance of ob/ob mice as compared with control mice. However, the co-treatment of the BMDMs with autophagy inhibitor 3-Methyladenine (3-MA) reversed the effect of BBR almost completely. Taken together, BBR exerted its anti-inflammatory effects through activation of AMPK-dependent autophagy in adipose tissue macrophages (ATMs). This study amplified the mechanisms of BBR and its potential in attenuating insulin resistance. (C) 2017 Published by Elsevier Masson SAS.